Priority is hereby claimed of previously filed foreign application, GB 0120808.1, filed Aug. 28, 2001 (37 C.F.R. xc2xa71.55(a)), which was filed under the Paris Convention for the Protection of Industrial Property and was filed in the United Kingdom with, and received by The Patent Office, Cardiff Road, Newport, South Wales, NP10 8QQ.
This invention relates to a new crystalline, pharmaceutically acceptable, form of amlodipine free base, processes for its synthesis and its use in pharmaceutical compositions.
Amlodipine, 2-[(2-aminoethoxy)]-methyl-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, is a calcium channel blocking agent with a long duration of action which has been approved world-wide, as its benzenesulfonate (besylate) salt, for use in the treatment of ischaemic heart disease and hypertension. The compound exists as (+/xe2x88x92) isomers, with most of the activity residing in the (xe2x88x92) isomer, which can be isolated by standard techniques, if so desired.
A number of European (EP) and International (WO) patent applications relate to amlodipine and its salts. Amlodipine and salts thereof were first disclosed by the present applicants in EP89167. The besylate salt of amlodipine was first disclosed in EP244944. WO01/02360, EP0902016, EP566142, EP599220 and Hungarian Patent Application No. 217346 describe processes for the preparation of salts of amlodipine. The free base formed is not isolated. WO99/52873 describes various organic and non-organic salts of amlodipine, but is silent on the free base. WO00/24714 describes processes for the preparation of the phthalimide derivatives of amlodipine, but is silent as to preparation or isolation of the free base. WO99/25688 describes the preparation of amlodipine free base prior to salt formation. However, no details are provided as to the physical form of the material, which is in a crude form from work-up of the reaction mixture and therefore, it is submitted, is likely to be in the form of an oil. U.S. Pat. No. 6,057,344 and EP1013275 describe methods of treatment comprising (xe2x88x92) amlodipine and its salts, although no preparation or isolation of the free base is described. WO99/11259 describes compositions comprising a combination of amlodipine and atorvastatin and is silent on any preparation of amlodipine free base.
In the non-patent literature, preparation of amlodipine, as its maleate salt, was first described in J. Med. Chem 1986, 29, 1696. A reaction scheme describing the production synthesis of amlodipine besylate via the free base is described in an undergraduate resource material entitled xe2x80x98Dihydropyridines In Actionxe2x80x99, Hobsons Publishing, 1989 (ISBN:/85324 280 2). No explicit reaction conditions are described to accompany the scheme.
It is submitted that none of the listed prior art explicitly discloses the preparation and characterisation of amlodipine free base in a solid form. The prior art comprises numerous disclosures of salt formations of amlodipine, which teaches away from the utility of amlodipine free base itself as a pharmaceutical product. In fact, solid free base initially synthesised by the present applicants xe2x80x98in-housexe2x80x99 was characterised as a poorly soluble and low-melting point material, which was unsuitable for formulation. Furthermore, amlodipine is known to undergo an internal reaction to afford a cyclic impurity rendering it unsuitable for formulation and it was hypothesised that solid amlodipine free base would undergo such a reaction. See scheme 1. 
When amlodipine is treated to form an addition salt with a strong acid, the propensity for the internal reaction is reduced due to protonation of the free amino group. Hence, the teaching of the prior art is to form addition salts with sufficiently strong acids such as benzene sulfonic acid or maleic acid and the result is a prejudice in the art away from the utility of free base material.
Surprisingly, the present inventors have found that amlodipine free base in a crystalline form can be prepared and has a melting point and, most surprisingly, a solubility profile which renders it suitable for pharmaceutical formulation. Such a solubility profile was unexpected, based on the xe2x80x98in-housexe2x80x99 knowledge of the properties of initially synthesised free base material. Furthermore, the crystalline material has sufficient stability for long term storage and use and does not undergo the internal reaction described above to any significant extent.
Thus, as a first aspect, the present invention provides a crystalline form of amlodipine free base. As a preferred aspect, the crystalline material is free from amorphous free base material.
Crystalline amlodipine free base according to the present invention has all the characteristics of a normal crystal structure, i.e. it forms a regular crystal lattice. It will be clear to the skilled person that materials which exist in a crystalline state may exist in a number of different polymorphic forms. Polymorphs may be identified by well-known techniques and all polymorphs of crystalline amlodipine free base are envisioned by the present invention. Crystals of amlodipine free base may be characterised in terms of their x-ray diffraction (XRD) pattern, which produces a read-out based on the lattice structure of the crystal. It is well known to those skilled in the art that different polymorphic forms of a material may be distinguished in terms of the XRD patterns.